Use of Pyridostigmine for Constipation in Diabetics

Pyridostigmine in Diabetics With Constipation: Randomized, Placebo-controlled, Double-blind Trial

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00276406

Enrollment

Registered

2006-01-13

Start date

2006-05-31

Completion date

2010-10-31

Last updated

2012-11-30

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Colonic Transit, Constipation, Diabetes Mellitus, Gastric Emptying

Brief summary

Doctors at Mayo Clinic are doing this study to learn if pyridostigmine, a drug, affects the speed at which food travels through the stomach, intestines and colon, and if pyridostigmine improves constipation symptoms in patients with diabetes. Pyridostigmine has been approved by the Food and Drug Administration (FDA) for routine clinical use, however, its use as proposed in this study is considered investigational.

Detailed description

Chronic constipation in diabetes mellitus is associated with colonic motor dysfunction and is managed with laxatives. Cholinesterase inhibitors increase colonic motility. The study evaluated the effects of a cholinesterase inhibitor (pyridostigmine vs. placebo) on gastrointestinal and colonic transit and bowel function in diabetic patients with constipation. After a 9-day baseline period, patients with diabetes mellitus and chronic constipation without defecatory disorder will be randomized to oral placebo or pyridostigmine, starting with 60 mg three times a day, increasing by 60 mg every third day up to the maximum tolerated dose of 120 mg three times a day; this dose will be maintained for 7 days. Gastrointestinal and colonic transit (assessed by scintigraphy) and bowel function will be evaluated at baseline and the final 3 and 7 days of treatment, respectively.

Interventions

DRUGPyridostigmine

Pyridostigmine will be started at (60mg) tid, increased over 10 days to 120 mg tid, and maintained at that dose for 7 days.

DRUGPlacebo

If subject is randomized to placebo, placebo pills will be started at (60mg) tid, increased over 10 days to 120 mg tid, and maintained at that dose for 7 days.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 70 Years

Healthy volunteers

Inclusion criteria

* Subjects with diabetes mellitus (Type I or type II), diagnosed by a physician. * On medical treatment for diabetes (oral medication or injected insulin) for at least one year * Symptomatic constipation at least 25% of the time in the past year (Rome II criteria for functional constipation) * 18-70 years of age * Colonoscopy negative for obstructive lesions, cancer, or inflammatory bowel disease (IBS) within the last 8 years if 50 years of age or older * Able to provide written informed consent before participating in trial * Able to communicate adequately with the Investigator and to comply with the requirements for the entire study

Exclusion criteria

* History of pelvic floor dysfunction (other functional GI disorders, eg IBS, non-ulcer dyspepsia are acceptable); Specifically, patients will be excluded if they have at least 2 of the following 3 criteria: * History of digital evacuation of the rectum or pressure on the posterior aspect of the vagina or perineum to facilitate defecation * Examination findings suggestive of puborectalis spasm or anismus, on assessment by an experienced gastroenterologist with expertise in this field; i.e. high anal sphincter tone at rest, failure of perineal descent by \>1cm on straining, and tenderness or paradoxical contraction of the puborectalis on digital examination * Requirement of \> 200g to expel a rectal balloon during voluntary straining * Abdominal surgery other than appendectomy, cholecystectomy, hysterectomy, tubal ligation, or inguinal hernia repair * Suspected or known gastrointestinal or genitourinary obstruction * Uncontrolled hypertension (defined as \> 150/90 at rest) * Known cardiac arrhythmia or ECG abnormalities, i.e. cardiac conduction disturbances (2nd or 3rd degree atrioventricular (AV) block, prolonged corrected QT interval (QTc)(\> 460 msec) or bradycardia (\< 45 beats/minute)) * Renal insufficiency with serum creatinine greater than 2 mg/dl based on a reading from the previous 6 months * Asthma or chronic obstructive pulmonary disease requiring systemic steroids in the previous 3 years (inhaled steroids acceptable) * Current use of narcotics, gut prokinetic drugs (eg metoclopramide, domperidone, tegaserod, senekot), anticholinergic medication (eg. Hyoscyamine, belladonna), antidiarrheals (Imodium, Lomotil), or laxatives other than fiber supplements, docusate, or glycerin suppositories. Patients on any of these restricted medications must cease use at least 48 hours before starting and for the duration of both study phases. No rescue laxatives will be permitted within 7 days of transit testing * Patients who have taken any investigational medications within the past 30 days * Known intolerance or allergy to eggs * Pregnant or breast-feeding females

Design outcomes

Primary

Measure	Time frame	Description
Colonic Geometric Center at 24 Hours (GC24) Measured by Scintigraphy	Baseline period (days 7-9 ), Treatment period (days 14-17)	The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images of the abdomen are taken hourly for the first 6 hours after the radio-labeled meal, then at 8, 24 and 48 hours. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit, a GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool. GC24 is the measurement taken at 24 hours after the radio-labeled meal.
Ascending Colon Emptying Half-time (AC t1/2) Measured in Hours	Baseline period (days 7-9 ), Treatment period (days 14-17)	Calculated by linear interpolation of values on the AC emptying curve.

Secondary

Measure	Time frame	Description
Colonic Geometric Center at 48 Hours (GC48) as Measured by Scintigraphy	Baseline period (days 7-9 ), Treatment period (days 14-17)	The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly for the first 6 hours after the radio-labeled meal, then at 8, 24 and 48 hours. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit, a GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool. GC48 is the measurement taken at 48 hours after the radio-labeled meal.
Stool Frequency Per Day	Daily during baseline period (9 days), Treatment period (7 days)	During 9 days of the baseline period and during 17 days of the treatment period, subjects used a daily diary to record the number of times per day they had a bowel movement. Only the 7 days of highest treatment dose will be used for comparison purposes.
Stool Form/Consistency	Daily during baseline period (9 days), Treatment period (7 days)	During 9 days of the baseline period and during 17 days of the treatment period, subjects used a daily diary to record a description of stool consistency according to the Bristol Stool Form Scale (ranging from 1 (hard lumps) to 7 (watery)). The Bristol Stool Scale is a medical aid designed to classify the form of human feces into seven categories or types. Types 1 and 2 indicate constipation with 3 and 4 being the ideal stools especially the latter, as they are the easiest to defecate, and 5-7 tending towards diarrhea.
Stool Ease of Passage	Daily during baseline period (9 days), Treatment period (7 days)	During 9 days of the baseline period and during 17 days of the treatment period, subjects used a daily diary to record a description of stool ease of passage of stool, according to the Bristol Stool Form Scale (ranging from 1 (manual disimpaction) to 7 (incontinence)). Only the 7 days at highest treatment dose will be used for comparison purposes.
Gastric Emptying Half-time (GE t1/2)	Baseline period (9 days), Treatment period (7 days)	The measure of time for 50 percent of a radio-labeled meal to empty from the stomach.
Stool Frequency Per Week	Daily during baseline period (9 days), Treatment period (7 days)	During 9 days of the baseline period and during 17 days of the treatment period, subjects used a daily diary to record the number of times per day they had a bowel movement. Complete spontaneous bowel movements per week are reported. Only the 7 days of highest treatment dose will be used for comparison purposes.
Heart Rate Before and After Treatment	Baseline period (9 days), Treatment period (7 days)	Heart rate is the number of beats per minute, as recording on an Electrocardiogram (ECG).
QTc Interval Before and After Treatment	Baseline period (9 days), Treatment period (7 days)	The corrected QT interval (QTc) is a measurement of time (seconds) between the Q and T waves of an heart beat as recorded during an Electrocardiogram (ECG).
Sense of Completely Emptying Bowels	Daily during baseline period (9 days), Treatment period (7 days)	During 9 days of the baseline period and during 17 days of the treatment period, subjects used a daily diary to record whether or not they felt they had completely emptied their bowels(1= Yes; 0= No). Only the 7 days of highest treatment dose will be used for comparison purposes.
Colonic Filling at 6 Hours	Baseline period (9 days), Treatment period (7 days)	The proportion of a radio-labeled meal in the colon at 6 hours (identifiable by radio-labelled tracer to capsule eaten with meal), measured by scintigraphy. This is an indirect measurement of small-bowel transit time.

Countries

United States

Participant flow

Recruitment details

Participants were recruited from Mayo Clinic in Rochester, Minnesota and the study was conducted at between May 2006 and October 2010.

Pre-assignment details

68 patients were assessed for eligibility. 24 were ineligible. 13 were eligible but declined to participate in the study. One patient consented but was withdrawn because of severe hyperglycemia during the baseline period. 30 were enrolled and completed all study procedures.

Participants by arm

Arm	Count
Pyridostigmine Oral pyridostigmine, starting with 60 mg capsules three times per day (tid), increasing by 60 mg every third day (i.e., over 10 days) up to the maximum tolerated dose or 120 mg tid (a total of 360 mg per day). This dose was maintained for 7 days.	16
Placebo Placebo (sham) capsules, matching the appearance of the active drug comparator and taken tid.	14
Total	30

Baseline characteristics

Characteristic	Pyridostigmine	Placebo	Total
Age Continuous	48.5 years STANDARD_DEVIATION 11.4	52.1 years STANDARD_DEVIATION 11.3	50.2 years STANDARD_DEVIATION 11.3
Body Mass Index	27.9 kilograms/meter^2 STANDARD_DEVIATION 4.4	31.6 kilograms/meter^2 STANDARD_DEVIATION 6	29.7 kilograms/meter^2 STANDARD_DEVIATION 5.5
Geometric Center (GC) of Colonic transit Geometric Center of Colonic Transit at 24 hr (GC24	1.96 Units on a scale STANDARD_DEVIATION 0.71	1.98 Units on a scale STANDARD_DEVIATION 0.62	1.97 Units on a scale STANDARD_DEVIATION 0.66
Geometric Center (GC) of Colonic transit Geometric Center of Colonic Transit at 48 hr (GC48	2.92 Units on a scale STANDARD_DEVIATION 0.89	2.97 Units on a scale STANDARD_DEVIATION 1	2.94 Units on a scale STANDARD_DEVIATION 0.93
Hemoglobin A1c	8.1 Percentage STANDARD_DEVIATION 1.7	7.7 Percentage STANDARD_DEVIATION 1.2	7.9 Percentage STANDARD_DEVIATION 0.3
Region of Enrollment United States	16 participants	14 participants	30 participants
Sex: Female, Male Female	13 Participants	9 Participants	22 Participants
Sex: Female, Male Male	3 Participants	5 Participants	8 Participants
Subjects with diabetic retinopathy	9 Participants	7 Participants	16 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	11 / 16	5 / 14
serious Total, serious adverse events	0 / 16	0 / 14

Outcome results

Primary

Ascending Colon Emptying Half-time (AC t1/2) Measured in Hours

Calculated by linear interpolation of values on the AC emptying curve.

Time frame: Baseline period (days 7-9 ), Treatment period (days 14-17)

Arm	Measure	Group	Value (MEAN)	Dispersion
Pyridostigmine	Ascending Colon Emptying Half-time (AC t1/2) Measured in Hours	Baseline	16.73 hours	Standard Error 2.3
Pyridostigmine	Ascending Colon Emptying Half-time (AC t1/2) Measured in Hours	Treatment	10.44 hours	Standard Error 1.4
Placebo	Ascending Colon Emptying Half-time (AC t1/2) Measured in Hours	Baseline	20.59 hours	Standard Error 3.29
Placebo	Ascending Colon Emptying Half-time (AC t1/2) Measured in Hours	Treatment	18.77 hours	Standard Error 3.23

Primary

Colonic Geometric Center at 24 Hours (GC24) Measured by Scintigraphy

The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images of the abdomen are taken hourly for the first 6 hours after the radio-labeled meal, then at 8, 24 and 48 hours. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit, a GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool. GC24 is the measurement taken at 24 hours after the radio-labeled meal.

Time frame: Baseline period (days 7-9 ), Treatment period (days 14-17)

Arm	Measure	Group	Value (MEAN)	Dispersion
Pyridostigmine	Colonic Geometric Center at 24 Hours (GC24) Measured by Scintigraphy	Baseline	1.96 units on a scale	Standard Error 0.18
Pyridostigmine	Colonic Geometric Center at 24 Hours (GC24) Measured by Scintigraphy	Treatment	2.45 units on a scale	Standard Error 0.2
Placebo	Colonic Geometric Center at 24 Hours (GC24) Measured by Scintigraphy	Treatment	1.84 units on a scale	Standard Error 0.16
Placebo	Colonic Geometric Center at 24 Hours (GC24) Measured by Scintigraphy	Baseline	1.98 units on a scale	Standard Error 0.17

Comparison: Analysis was adjusted for BMI and baseline values and incorporated Bonferroni corrections.p-value: <0.01ANCOVA

Secondary

Colonic Filling at 6 Hours

The proportion of a radio-labeled meal in the colon at 6 hours (identifiable by radio-labelled tracer to capsule eaten with meal), measured by scintigraphy. This is an indirect measurement of small-bowel transit time.

Time frame: Baseline period (9 days), Treatment period (7 days)

Arm	Measure	Group	Value (MEAN)	Dispersion
Pyridostigmine	Colonic Filling at 6 Hours	Baseline	37 percentage of meal	Standard Error 9
Pyridostigmine	Colonic Filling at 6 Hours	Treatment	53 percentage of meal	Standard Error 7
Placebo	Colonic Filling at 6 Hours	Treatment	48 percentage of meal	Standard Error 9
Placebo	Colonic Filling at 6 Hours	Baseline	41 percentage of meal	Standard Error 10

Secondary

Colonic Geometric Center at 48 Hours (GC48) as Measured by Scintigraphy

The scintigraphic method is used to measure colonic transit. An isotope is adsorbed on activated charcoal particles and delivered to the colon in a delayed release capsule. Anterior and posterior gamma images are taken hourly for the first 6 hours after the radio-labeled meal, then at 8, 24 and 48 hours. The geometric center (GC) is the weighted average of counts in the different colonic regions. The scale ranges from 1 to 5; a high GC implies faster colonic transit, a GC of 1 implies all isotope is in the ascending colon, and a GC of 5 implies all isotope is in the stool. GC48 is the measurement taken at 48 hours after the radio-labeled meal.

Time frame: Baseline period (days 7-9 ), Treatment period (days 14-17)

Arm	Measure	Group	Value (MEAN)	Dispersion
Pyridostigmine	Colonic Geometric Center at 48 Hours (GC48) as Measured by Scintigraphy	Baseline	2.92 units on a scale	Standard Error 0.22
Pyridostigmine	Colonic Geometric Center at 48 Hours (GC48) as Measured by Scintigraphy	Treatment	3.59 units on a scale	Standard Error 0.25
Placebo	Colonic Geometric Center at 48 Hours (GC48) as Measured by Scintigraphy	Baseline	2.97 units on a scale	Standard Error 0.27
Placebo	Colonic Geometric Center at 48 Hours (GC48) as Measured by Scintigraphy	Treatment	3.26 units on a scale	Standard Error 0.27

Comparison: Analysis was adjusted for BMI and baseline values and incorporated Bonferroni corrections.p-value: 0.096ANCOVA

Secondary

Gastric Emptying Half-time (GE t1/2)

The measure of time for 50 percent of a radio-labeled meal to empty from the stomach.

Time frame: Baseline period (9 days), Treatment period (7 days)

Arm	Measure	Group	Value (MEAN)	Dispersion
Pyridostigmine	Gastric Emptying Half-time (GE t1/2)	Baseline	142 minutes	Standard Error 19
Pyridostigmine	Gastric Emptying Half-time (GE t1/2)	Treatment	122 minutes	Standard Error 13
Placebo	Gastric Emptying Half-time (GE t1/2)	Baseline	141 minutes	Standard Error 12
Placebo	Gastric Emptying Half-time (GE t1/2)	Treatment	121 minutes	Standard Error 13.42

Secondary

Heart Rate Before and After Treatment

Heart rate is the number of beats per minute, as recording on an Electrocardiogram (ECG).

Time frame: Baseline period (9 days), Treatment period (7 days)

Arm	Measure	Group	Value (MEAN)	Dispersion
Pyridostigmine	Heart Rate Before and After Treatment	Baseline	74 beats per minute	Standard Error 3
Pyridostigmine	Heart Rate Before and After Treatment	Treatment	66 beats per minute	Standard Error 2
Placebo	Heart Rate Before and After Treatment	Baseline	76 beats per minute	Standard Error 4
Placebo	Heart Rate Before and After Treatment	Treatment	75 beats per minute	Standard Error 3

Secondary

QTc Interval Before and After Treatment

The corrected QT interval (QTc) is a measurement of time (seconds) between the Q and T waves of an heart beat as recorded during an Electrocardiogram (ECG).

Time frame: Baseline period (9 days), Treatment period (7 days)

Arm	Measure	Group	Value (MEAN)	Dispersion
Pyridostigmine	QTc Interval Before and After Treatment	Baseline	428 Milliseconds	Standard Error 6
Pyridostigmine	QTc Interval Before and After Treatment	Treatment	415 Milliseconds	Standard Error 18
Placebo	QTc Interval Before and After Treatment	Baseline	420 Milliseconds	Standard Error 8
Placebo	QTc Interval Before and After Treatment	Treatment	421 Milliseconds	Standard Error 4

Secondary

Sense of Completely Emptying Bowels

During 9 days of the baseline period and during 17 days of the treatment period, subjects used a daily diary to record whether or not they felt they had completely emptied their bowels(1= Yes; 0= No). Only the 7 days of highest treatment dose will be used for comparison purposes.